ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.715G>A (p.Glu239Lys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007194.4(CHEK2):c.715G>A (p.Glu239Lys)
Variation ID: 5600 Accession: VCV000005600.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28711986 (GRCh38) [ NCBI UCSC ] 22: 29107974 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 18, 2013 Aug 4, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.715G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Glu239Lys missense NM_001005735.2:c.844G>A NP_001005735.1:p.Glu282Lys missense NM_001257387.2:c.52G>A NP_001244316.1:p.Glu18Lys missense NM_001349956.2:c.514G>A NP_001336885.1:p.Glu172Lys missense NM_145862.2:c.715G>A NP_665861.1:p.Glu239Lys missense NC_000022.11:g.28711986C>T NC_000022.10:g.29107974C>T NG_008150.2:g.34881G>A LRG_302:g.34881G>A LRG_302t1:c.715G>A LRG_302p1:p.Glu239Lys O96017:p.Glu239Lys - Protein change
- E239K, E282K, E172K, E18K
- Other names
- chr22:29,107,974C>T
- p.E239K:GAG>AAG
- Canonical SPDI
- NC_000022.11:28711985:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00012
The Genome Aggregation Database (gnomAD) 0.00016
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CHEK2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4045 | 4100 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
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Apr 19, 2023 | RCV000114762.32 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Aug 21, 2023 | RCV000131201.26 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Mar 24, 2024 | RCV000205850.28 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2024 | RCV001818140.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 10, 2021 | RCV002476934.8 | |
Predisposition to cancer
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Uncertain significance (1) |
criteria provided, single submitter
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Apr 14, 2023 | RCV001789748.12 |
Uncertain significance (1) |
no assertion criteria provided
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Feb 1, 2003 | RCV003333689.2 | |
CHEK2-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV004532294.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Apr 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885199.1
First in ClinVar: Apr 24, 2014 Last updated: Apr 24, 2014 |
Comment:
The CHEK2: p.Glu239Lys variant (rs121908702) has been reported in association with colorectal, prostate, breast, and ovarian cancers, including control groups (Yurgelun 2017, Kraus 2017, Dong … (more)
The CHEK2: p.Glu239Lys variant (rs121908702) has been reported in association with colorectal, prostate, breast, and ovarian cancers, including control groups (Yurgelun 2017, Kraus 2017, Dong 2003, and Southey 2016). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.03 percent in the European Finnish population (identified on 8 out of 25,726 chromosomes) and has been reported to the ClinVar database (Variation ID: 5600). Reconstitution of this variant in yeast cells lacking CHEK2 showed a “moderate†decrease of growth compared to WT after DNA damage induction by methyl methanesulfonate (Roeb 2012). This variant is moderately conserved in the kinase domain of the CHEK2 protein and has been shown to reduce the phosphorylation activity of the enzyme with model substrate (Wu 2006); however computational predictors indicate a neutral effect on protein structure and function (SIFT: tolerated, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Glu239Lys variant with certainty. (less)
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Uncertain significance
(Jul 31, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002066146.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Uncertain significance
(Aug 11, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002537633.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CHEK2 c.715G>A(p.E239K) variant has been reported in individuals with breast, prostate, colon, or thyroid cancer (PMID: 21244692, 30303537, 27616075, 33471991, 32957588, 27595995, 12533788, 16941491, … (more)
The CHEK2 c.715G>A(p.E239K) variant has been reported in individuals with breast, prostate, colon, or thyroid cancer (PMID: 21244692, 30303537, 27616075, 33471991, 32957588, 27595995, 12533788, 16941491, 28135145, 33692755, among others). It has also been reported in healthy controls (PMID: 27595995, 33471991). It was observed in 24/282754 chromosomes, with no homozygotes, across all populations in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). Functional studies have shown reduced CHEK2 kinase activity (PMID: 16835864, 31780696, 31050813), while others have suggested this is a benign variant (PMID: 30851065). The variant has been reported in ClinVar (Variation ID: 5600). In silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Jul 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000839481.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Uncertain significance
(Nov 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Colorectal cancer Familial prostate cancer Bone osteosarcoma Li-Fraumeni syndrome 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000896947.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Uncertain significance
(Apr 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000210972.17
First in ClinVar: Apr 24, 2014 Last updated: Apr 30, 2023 |
Comment:
Published functional studies are conflicting: some demonstrate reduced or intermediate kinase activity, stability, and DNA damage response while others report activity similar to wild type … (more)
Published functional studies are conflicting: some demonstrate reduced or intermediate kinase activity, stability, and DNA damage response while others report activity similar to wild type (Wu et al., 2006; Roeb et al., 2012; Scarpa et al., 2017; Delimitsou et al., 2019; Dutil et al., 2019; Kleiblova et al., 2019; Boonen et al., 2022); Observed in individuals with a history of breast cancer, prostate cancer, colorectal cancer, non-Hodgkin lymphoma, or other cancers (Dong et al., 2003; Le Calvez-Kelm et al., 2011; Havranek et al., 2015; Kraus et al., 2016; Tung et al., 2016; Yurgelun et al., 2017; Dutil et al., 2019; Girard et al., 2019; Greville-Heygate et al., 2020; Dorling et al., 2021; Srivastava et al., 2021; Guindalini et al., 2022; McDonald et al., 2022; Wagener et al., 2022); Case control studies suggest this variant is not associated with breast, ovarian, or prostate cancer (Southey et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.844G>A, p.E282K; This variant is associated with the following publications: (PMID: 12533788, 21244692, 25318351, 16835864, 22419737, 23298314, 25525159, 16941491, 26506619, 26976419, 26787654, 28135136, 28135137, 27616075, 28199314, 28135145, 31050813, 30851065, 31780696, 32957588, 34426522, 27595995, 33309985, 33692755, 19782031, 32923877, 35264596, 33471991, 36315513, 30303537, 36468172, 34903604) (less)
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Uncertain significance
(Apr 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Predisposition to cancer
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002032285.3
First in ClinVar: Dec 18, 2021 Last updated: Jun 03, 2023 |
Comment:
The CHEK2 c.715G>A (p.Glu239Lys) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive and … (more)
The CHEK2 c.715G>A (p.Glu239Lys) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive and functional assays are not in agreement about the effect of this variant on protein function (PMID: 16835864, 22419737, 30851065, 31050813, 31780696, 34903604). This variant has been reported individuals with breast cancer (21244692, 27616075, 30303537) and prostate cancer (PMID: 12533788, 16835864). It is present 2x in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
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Uncertain significance
(Feb 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888122.5
First in ClinVar: Apr 24, 2014 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals affected with breast and/or ovarian cancer (PMIDs: 35264596 (2022), 33471991 (2021) see also LOVD … (more)
In the published literature, this variant has been reported in individuals affected with breast and/or ovarian cancer (PMIDs: 35264596 (2022), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2), 32957588 (2020), 30303537 (2019), 27616075 (2017), 27595995 (2016), 26976419 (2016), 26787654 (2016), 25186627 (2015), 21244692 (2011)), prostate cancer (PMIDs: 16941491 (2006), 12533788 (2003)), colorectal cancer (PMIDs: 33298767 (2021), 28135145 (2017)), as well as in healthy individuals (PMIDs: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2), 27595995 (2016)). In addition, functional studies in the published literature demonstrated that this variant has an intermediate effect on CHEK2 activity (PMIDs: 34903604 (2022), 30851065 (2019), 31050813 (2019), 31780696 (2019), 22419737 (2012), 16835864 (2006)), however further studies are needed to determine the global effect of this variant on CHEK2 protein activity. The frequency of this variant in the general population, 0.00025 (9/35436 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000262054.12
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 239 of the CHEK2 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 239 of the CHEK2 protein (p.Glu239Lys). This variant is present in population databases (rs121908702, gnomAD 0.03%). This missense change has been observed in individual(s) with prostate cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, colorectal cancer, non-medullary thyroid cancer, and/or breast cancer (PMID: 12533788, 21244692, 26506619, 26787654, 26976419, 27595995, 27616075, 28135145, 30303537, 31614935, 32957588, 33692755, 36468172). ClinVar contains an entry for this variant (Variation ID: 5600). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 16835864, 22419737, 30851065, 34903604). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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CHEK2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004711155.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The CHEK2 c.715G>A variant is predicted to result in the amino acid substitution p.Glu239Lys. This variant has been documented in individuals with prostate cancer (Dong … (more)
The CHEK2 c.715G>A variant is predicted to result in the amino acid substitution p.Glu239Lys. This variant has been documented in individuals with prostate cancer (Dong et al. 2003. PubMed ID: 12533788; Wu et al. 2006. PubMed ID: 16835864), breast cancer (Roeb et al. 2012. PubMed ID: 22419737) and ductal carcinoma in situ (Kraus et al. 2017, Supplemental Table 4. PubMed ID: 27616075). This variant has been reported to have a negative association with breast, prostate, and ovarian cancers among Europeans (Southey et al. 2016. PubMed ID: 27595995). Functional studies on this variant have indicated its possible role in altered acetylation (Suo et al. 2013. PubMed ID: 23298314), partially reduced kinase activity (Wu et al. 2006. PubMed ID: 16835864), and DNA damage response (Roeb et al. 2012. PubMed ID: 22419737). This variant is reported in 0.032% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/5600/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Jul 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004024652.2
First in ClinVar: Aug 19, 2023 Last updated: Aug 04, 2024 |
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Uncertain significance
(Apr 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004011387.10
First in ClinVar: Jul 16, 2023 Last updated: Aug 04, 2024 |
Comment:
CHEK2: PS3:Supporting
Number of individuals with the variant: 1
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Uncertain significance
(Mar 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698816.1
First in ClinVar: Apr 24, 2014 Last updated: Apr 24, 2014 |
Comment:
Variant summary: The CHEK2 c.715G>A (p.Glu239Lys) variant located in the kinase domain (via InterPro) involves the alteration of a conserved nucleotide and is predicted to … (more)
Variant summary: The CHEK2 c.715G>A (p.Glu239Lys) variant located in the kinase domain (via InterPro) involves the alteration of a conserved nucleotide and is predicted to be benign by 3/4 in silico tools (SNPs&GO not captured due to low reliability index). This variant was found in 19/209626 control chromosomes including broad and large populations from ExAC at a frequency of 0.0000906, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125). This variant has been reported as a germline variant in patients with breast cancer, ovarian cancer, prostate cancer and non-Hodgkin lymphoma (Dong 2003, Le Calvez-Kelm 2011, Tung_2015, Havranek 2015, Roeb_2015, Kraus_2016, Southey_2016). However, there are no cosegregation studies to confirm its pathogenicity or lack of pathogenicity. It has also been reported to co-occur with other rare missense variants, namely CHEK2 R346H, BRIP1 p.Arg416Trp, BRIP1 p.Ile640Thr (Calvez-Kelm_2011, Tung_2015) and BRCA1 p.Ser1715Cys (one internal sample). In a multicentre large case-control study, this variant was not found to confer a statistically significant increase risk for breast, ovarian and prostate cancers (Southey_2016). In the study, odds ratio for breast, ovarian and prostate cancers were 1.47 (95% CI: 0.6-3.64; p-value: 0.5), 1.47 (95% CI: 0.42-5.22; p-value: 0.54) and 1.47 (95% CI: 0.41-5.35; p-value: 0.55), respectively. Pathogenic variants in CHEK2 gene constitute risk alleles that confer low risk for breast cancer (e.g. CHEK2 1100delC leads to 2-3 fold increase in breast cancer risk in women and a 10 fold increase of risk in men; GeneReviews). Therefore, this variant could be an intermediate risk allele. This is also supported by functional studies that suggest this variant to have an intermediate effect in yeast-based in vivo DNA damage response and was found to partially reduce the kinase activity (Wu_2006, Roeb_2012). Multiple clinical diagnostic laboratories in ClinVar have classified this variant as uncertain significance. Taken together, this variant is currently classified as Variant of Unknown Significance (VUS). (less)
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Uncertain significance
(Nov 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000684682.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamic acid with lysine at codon 239 in the kinase domain of the CHEK2 protein. Computational prediction tool suggests that this … (more)
This missense variant replaces glutamic acid with lysine at codon 239 in the kinase domain of the CHEK2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown the mutant protein to exhibit partially reduced protein expression levels (PMID: 33606978), CHEK2 kinase activity (PMID: 16835864, 31050813, 31780696, 34903604) and DNA damage response (PMID: 22419737), but normal function in yeast complementation assay (PMID: 30851065). This variant has been observed in individuals affected with breast cancer (PMID: 21244692, 26976419, 27616075, 31780696, 32957588), colorectal cancer (PMID: 28135145), non-Hodgkin lymphoma (PMID: 26506619), prostate cancer (PMID: 12533788), papillary thyroid cancer (PMID: 33692755), and pheochromocytoma (PMID: 34630562). In large breast cancer case-control studies, this variant has not shown a conclusive association with increased risk of breast cancer (OR = 1.70, 95% CI 0.73 to 3.93, p=0.210 in PMID: 27595995; OR = 2.274, 95% CI 0.95 to 5.445, p=0.071 in PMID: 33471991). In addition, this variant has not shown significant association with ovarian cancer or prostate cancer in a large case-control study (PMID: 27595995). This variant has been identified in 24/282754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Aug 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000186151.10
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.E239K variant (also known as c.715G>A), located in coding exon 5 of the CHEK2 gene, results from a G to A substitution at nucleotide … (more)
The p.E239K variant (also known as c.715G>A), located in coding exon 5 of the CHEK2 gene, results from a G to A substitution at nucleotide position 715. The glutamic acid at codon 239 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in cohorts of prostate cancer patients, unselected non-Hodgkin lymphoma patients, and BRCA-negative HBOC patients (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Havranek O et al. PLoS ONE 2015 Oct;10(10):e0140819; Kraus C et al. Int. J. Cancer 2017 Jan;140(1):95-102; Girard E et al. Int J Cancer, 2019 04;144:1962-1974). In two large case-control studies, p.E239K was detected in breast cancer patients but not in healthy controls; however, these studies did not have enough carriers to demonstrate statistically increased odds (Girard E et al. Int J Cancer. 2019 04;144:1962-1974; Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6). In contrast, another case-control study identified p.E239K in 2/3360 healthy controls but not in 1928 breast cancer cases (Klieblova P et al. Int. J. Cancer. 2019 Oct;145(7):1782-1797). In another large study, this variant was reported in 18/60,466 breast cancer cases and in 7/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439) and in the combined case-control data in the ENIGMA CHEK2gether Project, this variant was reported in 15/73048 cases and 10/88658 controls, with insignificant OR of 1.63 (95% CI 0.68-4.06), p=0.24 (Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). Multiple functional studies have found that this alteration demonstrates partially reduced CHK2 kinase activity (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Klieblova P et al. Int. J. Cancer 2019 Oct;145(7):1782-1797; Boonen RACM et al. Cancer Res, 2022 02;82:615-631). However, in other studies, this variant was considered functional (Delimitsou A et al. Hum. Mutat. 2019 05;40(5):631-648; Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004217507.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(Feb 01, 2003)
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no assertion criteria provided
Method: literature only
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RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026130.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 14, 2023 |
Comment on evidence:
This variant, formerly titled TUMOR PREDISPOSITION SYNDROME 4, PROSTATE, has been reclassifed based on the report by Southey et al. (2016). In 1 of 298 … (more)
This variant, formerly titled TUMOR PREDISPOSITION SYNDROME 4, PROSTATE, has been reclassifed based on the report by Southey et al. (2016). In 1 of 298 men with familial prostate cancer (TPDS4; 609265), Dong et al. (2003) found a germline 715G-A transition in exon 5 of the CHEK2 gene, predicted to result in a glu239-to-lys (E239K) mutation in the kinase domain. The same mutation was found in 1 of 178 prostate cancer tumor samples. In a study on cancer susceptibility genes, Southey et al. (2016) found that the E239K variant was not associated with an increase of prostate cancer. The frequency of the variant in 22,301 white European men with prostate cancer and 22,320 controls was 0.00027 and 0.00018, respectively. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
germline,
somatic
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Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague
Accession: SCV000148657.1
First in ClinVar: Apr 24, 2014 Last updated: Apr 24, 2014
Comment:
Characterized in 1 out of 84 prostate tumour samples and in 1 out of 340 Non-Hodgkin lymphoma patients
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Observation 1: Observation 2: |
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Likely pathogenic
(Jun 26, 2023)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004044124.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16835864]. This variant is strongly associated with more severe personal … (more)
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16835864]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. (less)
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk. | Stolarova L | Clinical cancer research : an official journal of the American Association for Cancer Research | 2023 | PMID: 37449874 |
The CHK2 kinase is recurrently mutated and functionally impaired in the germline of pediatric cancer patients. | Wagener R | International journal of cancer | 2023 | PMID: 36468172 |
Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. | Guindalini RSC | Scientific reports | 2022 | PMID: 35264596 |
Functional Analysis Identifies Damaging CHEK2 Missense Variants Associated with Increased Cancer Risk. | Boonen RACM | Cancer research | 2022 | PMID: 34903604 |
Recurrent Germline Mutations of CHEK2 as a New Susceptibility Gene in Patients with Pheochromocytomas and Paragangliomas. | Gao Y | International journal of endocrinology | 2021 | PMID: 34630562 |
Whole Genome Sequencing Prioritizes CHEK2, EWSR1, and TIAM1 as Possible Predisposition Genes for Familial Non-Medullary Thyroid Cancer. | Srivastava A | Frontiers in endocrinology | 2021 | PMID: 33692755 |
Functional interrogation of DNA damage response variants with base editing screens. | Cuella-Martin R | Cell | 2021 | PMID: 33606978 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers. | Germani A | Journal of clinical medicine | 2020 | PMID: 32957588 |
Germline variants in cancer genes in high-risk non-BRCA patients from Puerto Rico. | Dutil J | Scientific reports | 2019 | PMID: 31780696 |
Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways. | Srivastava A | Biomolecules | 2019 | PMID: 31614935 |
Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. | Kleiblova P | International journal of cancer | 2019 | PMID: 31050813 |
Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. | Delimitsou A | Human mutation | 2019 | PMID: 30851065 |
Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. | Girard E | International journal of cancer | 2019 | PMID: 30303537 |
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. | Kraus C | International journal of cancer | 2017 | PMID: 27616075 |
PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. | Southey MC | Journal of medical genetics | 2016 | PMID: 27595995 |
Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. | Tung N | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 26976419 |
Multigene testing of moderate-risk genes: be mindful of the missense. | Young EL | Journal of medical genetics | 2016 | PMID: 26787654 |
Association of Germline CHEK2 Gene Variants with Risk and Prognosis of Non-Hodgkin Lymphoma. | Havranek O | PloS one | 2015 | PMID: 26506619 |
Use of panel tests in place of single gene tests in the cancer genetics clinic. | Yorczyk A | Clinical genetics | 2015 | PMID: 25318351 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Response to DNA damage of CHEK2 missense mutations in familial breast cancer. | Roeb W | Human molecular genetics | 2012 | PMID: 22419737 |
Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. | Le Calvez-Kelm F | Breast cancer research : BCR | 2011 | PMID: 21244692 |
Unique substitution of CHEK2 and TP53 mutations implicated in primary prostate tumors and cancer cell lines. | Zheng L | Human mutation | 2006 | PMID: 16941491 |
Characterization of CHEK2 mutations in prostate cancer. | Wu X | Human mutation | 2006 | PMID: 16835864 |
Mutations in CHEK2 associated with prostate cancer risk. | Dong X | American journal of human genetics | 2003 | PMID: 12533788 |
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Text-mined citations for rs121908702 ...
HelpRecord last updated Sep 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.